Benzodiazepines stimulate the α subunit of the postsynaptic γ-aminobutyric acid (GABAA) receptor in the CNS. Stimulation of this receptor affects the ligand-gated chloride channel on the cell membrane, altering the transmembrane resting potential to below stimulation threshold and rendering the postsynaptic neuron less excitable. Stimulation of this GABAA receptor leads to inhibitory effects throughout the neuraxis, producing the typical clinical effects of sedation, anxiolysis, anticonvulsant activity, and striated muscle relaxation.
In general, benzodiazepines are well absorbed from the GI tract. The onset of action after oral ingestion is limited more by the rate of absorption from the GI tract than by the relatively rapid passage from the bloodstream into the brain. With the exception of lorazepam and midazolam, IM injection of benzodiazepines results in unpredictable absorption. IV administration of midazolam and lorazepam has an onset of action in 1 to 5 minutes. Diazepam may be administered rectally, and midazolam may be administered intranasally or intrabuccally, with variable rates of absorption by those routes.
Benzodiazepines are relatively lipid-soluble, with some variation among the agents. Increased lipid solubility is associated with more rapid diffusion across the blood–brain barrier. After single doses, the more highly lipophilic benzodiazepines have a shorter onset of action but also a shorter duration of activity. This short duration of activity occurs because of rapid egress of the drug from the brain and bloodstream into inactive tissue storage sites. For this reason, the serum half-life is not a good indicator of the duration of action in an acute ingestion.
Benzodiazepine derivatives undergo hepatic metabolism through different pathways depending on the agent. Hepatic biotransformation occurs through either oxidation or conjugation; both pathways may be used by some derivatives. Oxidation often produces active metabolites that prolong the pharmacologic effects of the parent compounds. Oxidation is more susceptible to impairment by such factors as disease states (chronic liver disease), demographic characteristics (advanced age), and concurrent treatment with drugs that affect metabolism (estrogen, isoniazid, ethanol, ketoconazole, cimetidine, and phenytoin). Conjugation is a rapid process that generally produces inactive metabolites. Examples of agents that undergo conjugation primarily include lorazepam, oxazepam, and temazepam. These agents may be safer in these susceptible groups such as those patients with hepatic dysfunction.
There is conflicting evidence on how benzodiazepines affect fetal development.10,11,12 In general, the cohort studies did not find an increase in congenital malformations, but the case-control studies did show a small increase, especially for cleft lip and palate. This difference is ascribed to the higher sensitivity of case-control studies in identifying an association with specific conditions. The effect on fetal outcome of large doses of benzodiazepines taken for suicide attempts by pregnant women is not clear. Retrospective reviews of overdose with four different benzodiazepines, albeit with relatively small numbers, did not find an increased incidence of congenital abnormalities in the offspring.13,14,15,16
Chronic use of benzodiazepines during pregnancy can result in withdrawal syndrome in the infant after birth such as "floppy baby syndrome" (sedation, hypotonia, apnea, cyanosis, hypothermia) and neonatal withdrawal (restlessness, hypertonia, tremors).17 Nearly all benzodiazepines enter breast milk, and therefore, caution should be exercised in patients taking benzodiazepines.10,11
Administration of benzodiazepines in patients with comorbid conditions such as hepatic dysfunction or the elderly may cause significant effects. Those with hepatic dysfunction may have impaired metabolism, causing increased clinical effects. Elderly patients taking benzodiazepines are at increased risk for falls, cognitive impairment, delirium, fractures, and motor vehicle accidents.12,18
Drug–drug interactions with benzodiazepines occur mainly with drugs that affect the cytochrome P450 pathway, specifically CYP3A4 and CYP2C19. For example, drugs such as ketoconazole or cimetidine are CYP3A4 inhibitors and may increase benzodiazepine blood levels, increasing their duration of action and/or clinical effect. Benzodiazepines themselves have not been implicated in affecting cytochrome P450 enzymes and, therefore, are unlikely to interfere with metabolism of other agents.